This invention relates to the method of preventing and treating sepsis using certain chemokines alone or in conjunction with an anti-infective agent. This invention also relates to a new groxcex2 dimer chemokine.
Sepsis, as used herein, is broadly defined to mean situation when the invasion of a host by a microbial agent is associated with the clinical manifestations of infection including but not limited to: (1) temperature  greater than 38xc2x0 C. or  less than 36xc2x0 C.; (2) heart rate  greater than 90 beats per minute; (3) respiratory rate  greater than 20 beats per minute or PaCO2 less than 32 mm Hg; (4) white blood cell count  greater than 12,000/cu mm,  less than 4,000/cu mm, or  greater than 10% immature (band) forms; (5) organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oliguria, or an alteration in mental states. (Chest 1992; 101: 1644-1566)
Sepsis can occur in hospitalized patients having underlying diseases or conditions that render them susceptible to bloodstream invasion or in burn, trauma or surgical patents. In many cases of sepsis, the predominant pathogen is Escherichia coli, followed by other Gram-negative bacteria such as the Klebsiella-Enterobacter-Serratia group and then Pseudomonas. Although comprising a somewhat smaller percentage of infection, Gram-positive microbes such as Staphylococcus and systemic viral and fungal infections are included by the term sepsis as used herein. The genitourinary trait is the most common site of infection, the gastrointestinal tract and respiratory tract being the next most frequent sources of sepsis. Other common foci are wound, burn, and pelvic infections and infected intravenous catheters.
A serious consequence of bacterial sepsis often is septic sock. Septic shock is characterized by inadequate tissue perfusion, leading to insufficient oxygen supply to tissues, hypotension and oliguria.
Septic shock occurs because bacterial products react with cells and components of the coagulation, complement, fibrinolytic and bradykinin systems to release proteases which injure cells and alter blood flow, especially in the capillaries.
Microorganisms frequently activate the classical complement pathway, and endotoxin activates the alternative pathway. Complement activation, leukotriene generation and the direct effects of bacterial products on neutrophils lead to accumulation of these inflammatory cells in the lungs, release of their proteolytic enzyme and toxic oxygen radicals which damage the pulmonary endothelium and initiate the adult respiratory distress syndrome (xe2x80x9cARDSxe2x80x9d). ARDS is a major cause of death in patients with septic shock and is characterized by pulmonary congestion, granulocyte aggregation, hemorrhage and capillary thrombi.
Septic shock is a major cause of death in intensive care units. There are an estimated 200,000 cases per year of septic shock in the United States, and despite advances in technology (i.e., respiratory support) and antibiotic therapy, the mortality rate for septic shock remains in excess of 40%. In fact, mortality for established septic shock has decreased very little since the comprehensive description by Waisbren (Arch. Intern. Med. 88:467-488 (1951)). Although effective antibiotics are available, and there is an increased awareness of the septic shock syndrome, the incidence of septic shock the last several decades has actually increased. With the appreciation that antimicrobial agents have failed to completely abrogate septic mortality, it is clear that other agents must be developed to be used alone or in conjunction with antimicrobials in order to rectify the deficiencies of current established therapy.
This invention relates to a method of preventing or treating sepsis comprising administering to a human or non-human animal in need thereof amount of a protein derived from a chemokine selected from KC, groxcex1, groxcex2, and groxcex3. Most preferably, the chemokines used in the method of the invention include modified KC [amino acids 5-72 of the full length protein, SEQ ID NO: 1], an groxcex2 [amino acids 5-73 of the full length protein, SEQ ID NO: 3] or modified human groxcex3 [amino acids 5-73 of the full length protein, SEQ ID NO: 4] or multimers thereof. Most preferred is a covalently bonded dimer of two modified groxcex2 chemokines [amino acids 5-73 of the full length protein SEQ ID NO: 3]. Alternatively, the mature chemokines may be utilized in the method of the invention.
The method of the invention may be performed alone, or in conjunction with administration of an anti-infective agent.